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Journal ArticleDOI

Δ9-Tetrahydrocannabinol discrimination: Effects of route of administration in rats.

23 Jun 2021-Drug and Alcohol Dependence (Elsevier)-Vol. 225, pp 108827
TL;DR: In this article, the effects of route of administration (ROA) of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, were examined.
About: This article is published in Drug and Alcohol Dependence.The article was published on 2021-06-23. It has received 5 citations till now.
Citations
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Journal ArticleDOI
TL;DR: In this paper, a review of interoceptive processes related to alcohol is presented, including physiological responses to alcohol, how interceptive states can impact drinking, and the recruitment of brain networks as informed by clinical research.

6 citations

Journal ArticleDOI
TL;DR: In this article , the authors used liquid chromatography/tandem mass spectrometry to quantify the drug and its first-pass metabolites in nasal mucosa, lungs, plasma, and brain (olfactory bulb and cerebellum) at various time points after exposure.
Abstract: Passive aerosol exposure to Δ9-tetrahydrocannabinol (THC) in laboratory animals results in faster onset of action and less extensive liver metabolism compared to most other administration routes and might thus provide an ecologically relevant model of human cannabis inhalation. Previous studies have, however, overlooked the possibility that rodents, as obligate nose breathers, may accumulate aerosolized THC in the nasal cavity, from where the drug might directly diffuse to the brain. To test this, we administered THC (ten 5-s puffs of 100 mg/mL of THC) to adolescent (31-day-old) Sprague-Dawley rats of both sexes. We used liquid chromatography/tandem mass spectrometry to quantify the drug and its first-pass metabolites – 11-hydroxy-Δ9-THC (11-OH-THC) and 11-nor-9-carboxy-Δ9-THC (11-COOH-THC) – in nasal mucosa, lungs, plasma, and brain (olfactory bulb and cerebellum) at various time points after exposure. Apparent maximal THC concentration and area under the curve were ∼5 times higher in nasal mucosa than in lungs and 50–80 times higher than in plasma. Concentrations of 11-OH-THC were also greater in nasal mucosa and lungs than other tissues, whereas 11-COOH-THC was consistently undetectable. Experiments with microsomal preparations confirmed local metabolism of THC into 11-OH-THC (not 11-COOH-THC) in nasal mucosa and lungs. Finally, whole-body exposure to THC deposited substantial amounts of THC (∼150 mg/g) on fur but suppressed post-exposure grooming in rats of both sexes. The results indicate that THC absorption and metabolism in nasal mucosa and lungs, but probably not gastrointestinal tract, contribute to the pharmacological effects of aerosolized THC in male and female rats.

3 citations

Journal ArticleDOI
01 Jan 2021
TL;DR: Silva et al. as mentioned in this paper found that chlorpyrifos (CPF) exposure was associated with increased body weights, dysbiosis, inflammation and oxidative stress, potentially associated with an increased eCB acting through the gut-microbiota-adipose-brain regulatory loop.
Abstract: Marilyn Silva. Retired from a career in toxicology and risk assessment. Increased childhood and adult obesity are associated with chlorpyrifos (CPF), an organophosphate pesticide. Cannabis (Δ9Tetrahydrocannabinol: Δ9THC) use has increased globally with legalization. CPF applications on cannabis crops lacks federally regulated tolerances and may pose health risks through exposure during development and in adulthood. Both CPF and Δ9THC affect the endocannabinoid system (eCBS), a regulator of appetite, energy balance, and gut microbiota, which, if disrupted, increases risk for obesity and related diseases. CPF inhibits eCB metabolism and Δ9THC is a partial agonist/antagonist at the cannabinoid receptor (CB1R). Effects of each on obesogenic parameters were examined via literature search. Male rodents with CPF exposure showed increased body weights, dysbiosis, inflammation and oxidative stress, potentially associated with increased eCBs acting through the gut-microbiota-adipose-brain regulatory loop. Δ9THC generally decreased body weights via partial agonism at the CB1R, lowering levels of eCBs. Dysbiosis and/or oxidative stress associated inflammation occurred with CPF, but these parameters were not tested with Δ9THC. Database deficiencies included limited endpoints to compare between chemicals/age-groups, inter-study variables (dose ranges, dosing vehicle, rodent strain, treatment duration, etc.). CPF and Δ9THC were not tested together, but human co-chemical effects would depend on exposure ratio, subject age, exposure duration, and health status, among others. An overriding concern is that both chemicals are well-documented developmental neurotoxins in addition to their low dose effects on energy balance. A co-exposure risk assessment is warranted with increased use and lack of federal CPF regulation on cannabis.

2 citations

Posted ContentDOI
24 Sep 2021-bioRxiv
TL;DR: In this article, the authors used a vapor inhalation model in rats to test chronic THC vapor inhaling effects on thermal nociception and mechanical sensitivity, as well as midbrain (i.e., periaqueductal gray [PAG]) neuronal function, in adult male rats with chronic inflammatory pain.
Abstract: To reduce reliance on opioids for the treatment of pain in the clinic, ongoing work is testing the utility of cannabinoid drugs as a potential alternative for treatment of chronic pain and/or as a strategy for reducing opioid drug dosage and duration of treatment (i.e., so-called opioid-sparing effects). Previous preclinical work has shown robust anti-hyperalgesic effects of systemic THC and acute anti-hyperalgesic effects of vaporized THC. Here, we used a vapor inhalation model in rats to test chronic THC vapor inhalation effects on thermal nociception and mechanical sensitivity, as well as midbrain (i.e., periaqueductal gray [PAG]) neuronal function, in adult male rats with chronic inflammatory pain. We report that chronic THC vapor inhalation produces a robust anti-hyperalgesic effect in rats with chronic inflammatory pain, and that this effect persists 24 hours after cessation of THC exposure. We demonstrate that chronic THC vapor inhalation also modulates intrinsic and synaptic properties of ventrolateral PAG (vlPAG) neurons, including reductions in action potential firing rate and reductions in spontaneous inhibitory synaptic transmission, and that these effects occur specifically in neurons that respond to current input with a delayed firing phenotype. Finally, we show that the suppressive effect of the bath-applied mu-opioid receptor (MOR) agonist DAMGO on synaptic inhibition in the vlPAG is enhanced in slices taken from rats with a history of chronic THC vapor inhalation. Collectively, these data show that chronic THC vapor inhalation produces lasting attenuation of thermal hyperalgesia and reduces synaptic inhibition in the vlPAG of rats with chronic inflammatory pain.
References
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Book
01 Feb 1996

13,908 citations

Journal ArticleDOI
TL;DR: The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in the in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience.
Abstract: [3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

2,179 citations

Journal ArticleDOI
TL;DR: SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor and should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.

1,764 citations

Journal ArticleDOI
TL;DR: The results suggest that CB1 and CB2 can be considered as tissue-selective antigens of the central nervous system and immune system, respectively, and cannabinoids may exert specific receptor-mediated actions on the immune system through the CB2 receptor.
Abstract: Two proteins with seven transmembrane-spanning domains typical of guanosine-nucleotide-binding-protein-coupled receptors have been identified as cannabinoid receptors; the central cannabinoid receptor, CB1, and the peripheral cannabinoid receptor, CB2, initially described in rat brain and spleen, respectively. Here, we report the distribution patterns for both CB1 and CB2 transcripts in human immune cells and in several human tissues, as analysed using a highly sensitive and quantitative PCR-based method. CB1 was mainly expressed in the central nervous system and, to a lower extent, in several peripheral tissues such as adrenal gland, heart, lung, prostate, uterus, ovary, testis, bone marrow, thymus and tonsils. In contrast, the CB2 gene, which is not expressed in the brain, was particularly abundant in immune tissues, with an expression level 10-100-fold higher than that of CB1. Although CB2 mRNA was also detected in some other peripheral tissues, its level remained very low. In spleen and tonsils, the CB2 mRNA content was equivalent to that of CB1 mRNA in the central nervous system. Among the main human blood cell subpopulations, the distribution pattern of the CB2 mRNA displayed important variations. The rank order of CB2 mRNA levels in these cells was B-cells > natural killer cells >> monocytes > polymorphonuclear neutrophil cells > T8 cells > T4 cells. The same rank order was also established in human cell lines belonging to the myeloid, monocytic and lymphoid lineages. The prevailing expression of the CB2 gene in immune tissues was confirmed by Northern-blot analysis. In addition, the expression of the CB2 protein was demonstrated by an immunohistological analysis performed on tonsil sections using specific anti-(human CB2) IgG; this experiment showed that CB2 expression was restricted to B-lymphocyte-enriched areas of the mantle of secondary lymphoid follicles. These results suggest that (a) CB1 and CB2 can be considered as tissue-selective antigens of the central nervous system and immune system, respectively, and (b) cannabinoids may exert specific receptor-mediated actions on the immune system through the CB2 receptor.

1,646 citations

Journal ArticleDOI
14 Oct 2005-Science
TL;DR: These functional CB2 receptors in the brainstem were activated by a CB2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB1 receptors.
Abstract: The presence and function of CB2 receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB2 receptor messenger RNA and protein localization on brainstem neurons. These functional CB2 receptors in the brainstem were activated by a CB2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB1 receptors. CB2 receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.

1,466 citations